Intravenous Thrombolysis in Posterior versus Anterior Circulation Stroke: Clinical Outcome Differs Only in Patients with Large Vessel Occlusion.

The safety and efficacy of intravenous thrombolysis (IVT) are well established in anterior circulation stroke (ACS) but are much less clear for posterior circulation stroke (PCS). The aim of this study was to evaluate the occurrence of parenchymal hematoma (PH) and 3-month clinical outcomes after IVT in PCS and ACS. In an observational, cohort multicenter study, we analyzed data from ischemic stroke patients treated with IVT prospectively collected in the SITS (Safe Implementation of Treatments in Stroke) registry in the Czech Republic between 2004 and 2018. Out of 10,211 patients, 1166 (11.4%) had PCS, and 9045 (88.6%) ACS. PH was less frequent in PCS versus ACS patients: 3.6 vs. 5.9%, odds ratio (OR) = 0.594 in the whole set, 4.4 vs. 7.8%, OR = 0.543 in those with large vessel occlusion (LVO), and 2.2 vs. 4.7%, OR = 0.463 in those without LVO. At 3 months, PCS patients compared with ACS patients achieved more frequently excellent clinical outcomes (modified Rankin scale [mRS] 0-1: 55.5 vs. 47.6%, OR = 1.371 in the whole set and 49.2 vs. 37.6%, OR = 1.307 in those with LVO), good clinical outcomes (mRS 0-2: 69.9 vs. 62.8%, OR = 1.377 in the whole set and 64.5 vs. 50.5%, OR = 1.279 in those with LVO), and had lower mortality (12.4 vs. 16.6%, OR = 0.716 in the whole set and 18.4 vs. 25.5%, OR = 0.723 in those with LVO) (p < 0.05 in all cases). In PCS versus ACS patients, an extensive analysis showed a lower risk of PH both in patients with and without LVO, more frequent excellent and good clinical outcomes, and lower mortality 3 months after IVT in patients with LVO.

Development and Characterization of an In Vitro Intestinal Model Including Extracellular Matrix and Macrovascular Endothelium.

In vitro intestinal models are used to study biological processes, drug and food absorption, or cytotoxicity, minimizing the use of animals in the laboratory. They usually consist of enterocytes and mucus-producing cells cultured for 3 weeks, e.g., on Transwells, to obtain a fully differentiated cell layer simulating the human epithelium. Other important components are the extracellular matrix (ECM) and strong vascularization. The former serves as structural support for cells and promotes cellular processes such as differentiation, migration, and growth. The latter includes endothelial cells, which coordinate vascularization and immune cell migration and facilitate the transport of ingested substances or drugs to the liver. In most cases, animal-derived hydrogels such as Matrigel or collagen are used as ECM in in vitro intestinal models, and endothelial cells are only partially considered, if at all. However, it is well-known that animal-derived products can lead to altered cell behavior and incorrect results. To circumvent these limitations, synthetic and modifiable hydrogels (Peptigel and Vitrogel) were studied here to mimic xenofree ECM, and the data were compared with Matrigel. Careful rheological characterization was performed, and the effect on cell proliferation was investigated. The results showed that Vitrogel exhibited shear-thinning behavior with an internal structure recovery of 78.9 ± 11.2%, providing the best properties among the gels investigated. Therefore, a coculture of Caco-2 and HT29-MTX cells (ratio 7:3) was grown on Vitrogel, while simultaneously endothelial cells were cultured on the basolateral side by inverse cultivation. The model was characterized in terms of cell proliferation, differentiation, and drug permeability. It was found that the cells cultured on Vitrogel induced a 1.7-fold increase in cell proliferation and facilitated the formation of microvilli and tight junctions after 2 weeks of cultivation. At the same time, the coculture showed full differentiation indicated by high alkaline phosphatase release of Caco-2 cells (95.0 ± 15.9%) and a mucus layer produced by HT29-MTX cells. Drug tests led to ex vivo comparable permeability coefficients (Papp) (i.e., Papp; antipyrine = (33.64 ± 5.13) × 10-6 cm/s, Papp; atenolol = (0.59 ± 0.16) × 10-6 cm/s). These results indicate that the newly developed intestinal model can be used for rapid and efficient assessment of drug permeability, excluding unexpected results due to animal-derived materials.

Endovascular treatment for acute ischemic stroke in patients with tandem lesion in the anterior circulation: analysis from the METRICS study.

BACKGROUND: Acute ischemic stroke (AIS) due to anterior circulation tandem lesion (TL) remains a technical and clinical challenge for endovascular treatment (EVT). Conflicting results from observational studies and missing evidence from the randomized trials led us to report a recent real-world multicenter clinical experience and evaluate possible predictors of good outcome after EVT. METHODS: We analyzed all AIS patients with TL enrolled in the prospective national study METRICS (Mechanical Thrombectomy Quality Indicators Study in Czech Stroke Centers). A good 3-month clinical outcome was scored as 0-2 points in modified Rankin Scale (mRS), achieved recanalization using the Thrombolysis In Cerebral Infarction (TICI) scale and symptomatic intracerebral hemorrhage (sICH) according to the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) criteria. RESULTS: Of 1178 patients enrolled in METRICS, 194 (19.2%) (59.8% males, mean age 68.7±11.5 years) were treated for TL. They did not differ in mRS 0-2 (48.7% vs 46.7%; p=0.616), mortality (17.3% vs 22.7%; p=0.103) and sICH (4.7% vs 5.1%; p=0.809) from those with single occlusion (SO). More TL patients with prior intravenous thrombolysis (IVT) reached TICI 3 (70.3% vs 50.8%; p=0.012) and mRS 0-2 (55.4% vs 34.4%; p=0.007) than those without IVT. No difference was found in the rate of sICH (6.2% vs 1.6%; p=0.276). Multivariate logistic regression analysis showed prior IVT as a predictor of mRS 0-2 after adjustment for potential confounders (OR 3.818, 95% CI 1.614 to 9.030, p=0.002). CONCLUSION: Patients with TL did not differ from those with SO in outcomes after EVT. TL patients with prior IVT had more complete recanalization and mRS 0-2 and IVT was found to be a predictor of good outcome after EVT.

Modified Stability of microRNA-Loaded Nanoparticles.

microRNAs represent promising drugs to treat and prevent several diseases, such as diabetes mellitus. microRNA delivery brings many obstacles to overcome, and one strategy to bypass them is the manufacturing of self-assembled microRNA protein nanoparticles. In this work, a microRNA was combined with the cell-penetrating peptide protamine, forming so-called proticles. Previous studies demonstrated a lack of microRNA dissociation from proticles. Therefore, the goal of this study was to show the success of functionalizing binary proticles with citric acid in order to reduce the binding strength between the microRNA and protamine and further enable sufficient dissociation. Thus, we outline the importance of the present protons provided by the acid in influencing colloidal stability, achieving a constant particle size, and monodispersing the particle size distribution. The use of citric acid also provoked an increase in drug loading. Against all expectations, the AFM investigations demonstrated that our nanoparticles were loose complexes mainly consisting of water, and the addition of citric acid led to a change in shape. Moreover, a successful reduction in binding affinity and nanoparticulate stability are highlighted. Low cellular toxicity and a constant cellular uptake are demonstrated, and as uptake routes, active and passive pathways are discussed.

Intraoperative neurophysiological monitoring during urgent surgical extracranial internal carotid artery recanalization.

OBJECTIVE: The clinical outcome of surgical extracranial internal carotid artery (eICA) recanalization may be adversely affected by intraoperative ischemia. Median nerve somatosensory evoked potential (SEP) amplitude correlates well with cerebral blood flow. Our study presents the value of intraoperative SEP and selective shunting in the prevention of intraoperative ischemia development during urgent eICA recanalization. METHODS: Prospective recruitment of patients with acute unilateral eICA occlusion. All underwent surgical recanalization with intraoperative monitoring of scalp median SEPs. Preoperative clinical findings, cerebral collaterals, and 3 month functional outcome were evaluated. RESULTS: The cohort consisted of 33 patients. Intraoperative SEP amplitude decreased significantly in 6 (18.2%). An intraluminal shunt was inserted twice (6.1%), surgical complications occurred in 6 (18.2%), intracerebral hemorrhage was not found. Favorable outcome 3 months after surgery according to the modified Rankin scale (mRS 0-2) was achieved in 28 (84.8%), 3 patients died (9.1%). CONCLUSIONS: Intraoperative SEP during urgent eICA recanalization seems to be beneficial. Thanks to the effective measure based on the intraoperative SEP changes, the clinical outcome in four(12.1%) could be positively affected. SIGNIFICANCE: The results suggest that selective shunting based on intraoperative median SEPs may prevent intraoperative ischemia and may improve overall outcome of urgent eICA recanalization.

Mechanical Thrombectomy Quality Indicators Study in Czech Stroke Centers: Results of the METRICS Study.

BACKGROUND AND PURPOSE: Rigorous and regular evaluation of defined quality indicators is crucial for further improvement of both technical and clinical results after mechanical thrombectomy (MT) for acute ischemic stroke (AIS). Following the recent international multi-society consensus quality indicators, we aimed to assess trend in these indicators on national level. MATERIAL AND METHODS: The prospective multicenter study (METRICS) was conducted in Czech Republic (CR) in year 2019. All participating centers collected technical and clinical data including defined quality indicators and results were subsequently compared with those from year 2016. RESULTS: In the 2019, 1375 MT were performed in the CR and 1178 (86%) patients (50.3% males, mean age 70.5 ± 13.0 years) were analyzed. Recanalization (TICI 2b-3) was achieved in 83.7% of patients and 46.2% of patients had good 3-month clinical outcome. Following time intervals were shortened in comparison to 2016: "hospital arrival - GP" (77 vs. 53 min; p<0.0001), "hospital arrival - maximal achieved recanalization" (122 vs. 93 min; p<0.0001), and "stroke onset - maximal achieved recanalization" (240 vs. 229 min; p p<0.0001). More patients with tandem occlusion were treated in 2019 (7.8 vs. 16.5%; p<0.0001) and more secondary transports were in 2019 (31.3 vs. 37.8%; p=0.002). No difference was found in 3-month clinical outcome and in the rate of periprocedural complications. Results of the METRICS study met all criteria of multi-society consensus quality indicators. CONCLUSION: Nationwide comparison between 2016 and 2019 showed improvement in the key time intervals, but without better overall clinical outcomes after MT.

Median somatosensory evoked potential as a predictor of clinical outcome after urgent surgical extracranial internal carotid artery recanalization.

OBJECTIVE: Changes in the N20/P25 amplitude of somatosensory evoked potentials (SEP) of the median nerve have been found to correlate with those in cortical regional cerebral blood flow (rCBF). Our study presents the use of median nerve SEP amplitude in predicting the clinical outcome of urgent surgical internal carotid artery (ICA) recanalization. METHODS: A total of 27 patients suffering an acute ischemic stroke (AIS) with extracranial ICA occlusion within 24 h were prospectively recruited. The primary preoperative endpoints included the SEP amplitude absolute value (SEP-amp) and the SEP amplitude side-to-side ratio (SEP-ratio). Clinical outcome at 3 months postoperatively was assessed using the modified Rankin scale (mRS-3M). RESULTS: The positive predictive values (PPVs) for SEP-amp and SEP-ratio were 95.5% and 100%, respectively, with the negative predictive values (NPVs) being 60.0% and 100%, respectively. The SEP-ratio correlated fully with mRS-3M. CONCLUSION: The median SEP side-to-side N20/P25 amplitude ratio seems to be a very strong positive and negative predictor of the clinical outcome of urgent recanalization of an extracranial ICA occlusion. SIGNIFICANCE: The results suggest that cortical evoked activity may help in selection patient for surgical recanalization and predict clinical recovery after an acute ischemic stroke.

Blood Flow Volume Measurement in Cervical and Intracranial Arteries using Quantitative Magnetic Resonance Angiography and Duplex Sonography (Bocaccia) - A Prospective Observational Study.

PURPOSE: Cerebral blood flow volume is an important factor for the accurate diagnosis of neurovascular diseases and treatment indication. This study aims to assess correlations of blood flow volume measurements in cervical and intracranial arteries between duplex sonography and quantitative magnetic resonance angiography (qMRA). MATERIALS AND METHODS: Consecutive patients with suspicion of cerebral vascular pathology underwent qMRA and duplex sonography of cervical and intracranial arteries with measurement of blood flow volume in bilateral common (CCA), internal (ICA) and external carotid arteries, vertebral and basilar arteries, middle, anterior, posterior cerebral and posterior communicating arteries using 2 different ultrasound machines. Ten patients underwent all examinations twice. Correlations between blood flow volume measurements were evaluated using Spearman's correlation coefficient and inter-class correlation coefficient (ICC). RESULTS: In total, 21 subjects (15 males, mean age: 56.3 ± 6.2 years) were included in the study. Duplex sonography inter-investigator correlation was excellent (ICC = 0.972, p < 0.0001) as well as intra-investigator correlations of both qMRA and duplex sonography (ICC ˃ 0.990, p < 0.0001). Mostly high correlations were recorded between qMRA and duplex sonography in particular cervical arteries but only low to moderate correlations were obtained for intracranial arteries. The mean differences between blood flow volume measurements were 10.9 ±â€Š8.1 % in the CCA and its branches when using qMRA and 15.0 ±â€Š11.9 % when using duplex sonography, 13.5 ±â€Š11.8 %/35.4 ±â€Š34.2 % in the ICA siphon and its branches when using qMRA/duplex sonography, and 24.1 ±â€Š19.7 %/44.9 ± 44.0 % in both vertebral arteries and the basilar artery when using qMRA/duplex sonography. CONCLUSION: Duplex sonography as well as qMRA allow for highly reproducible measurement of blood flow volume in cervical and intracranial arteries in routine clinical practice.

Enhanced composting as a way to a climate-friendly management of coffee by-products.

This study investigated the performance of aerobic windrow systems by using coffee by-products and green waste to reduce gaseous emissions. Thereafter, a comparison with the current treatment and gaseous emissions at a Coffee Mill in Costa Rica was made. Two different studies where performed in Germany (pile I and II) and one study in a Coffee Mill in Costa Rica (pile III). Temperature, water content, and pH were the key parameters controlled over 35 days in all the systems. Moreover, CH4 emission rates were quantified by a FTIR and by a portable gas detector device where the emissions reached values 100 times higher when coffee by-products as a unique material for the composting process was used. Results show that highest emission rates during the composting process for pile I was 0.007 g(m2)-1 h-1, for pile II 0.006 g(m2)-1 h-1, and for pile III 3.1 g(m2)-1 h-1. It was found that CH4 emissions could be avoided if the mixture and the formation of the windrow piles were performed following the key parameter for composting, and the usage of additional material is used. With this, the reduction of CH4 emissions at the Mill in Costa Rica could be achieved in the future.

Comparison of PEGylated and non-PEGylated proticles: An in vitro and in vivo study.

The development of so-called Proticles opens attractive possibilities for new drug delivery systems. Proticles are nanoparticles (NPs), which are formed by self-assembly of negatively charged oligonucleotides in combination with the positively charged peptide protamine. Polyethylene glycol (PEG) is a widely known pharmaceutical agent to stop particle growth and prolong circulation half-life of drug delivery systems. Therefore, two different NP formulations - one PEGylated and one non-PEGylated - were used in this work to gain information about the biological stability and half-life in circulation of Proticles. Thus, this study presents data of in vitro stability and in vivo pharmacokinetics of both, non-PEGylated and PEGylated Proticles radiolabeled with 111InCl3. The study demonstrated that successful radiolabeling of both Proticle-formulations was performed resulting in high radiochemical yields (> 85 %). Furthermore, the influence of PEGylation on the in vitro stability of 111In-radiolabeled NPs was investigated. No significant difference due to PEGylation was found. Unlike in vitro results, non-PEGylated 111In-Proticles seemed to degrade faster in vivo than PEGylated 111In-proticles, resulting in significantly higher blood values (111In-PEG-proticles: 0.23 ±â€¯0.01 % ID/g 1 h p.i.; 111In-proticles: 0.06 ±â€¯0.01 % ID/g 1 h p.i.; p < 0.05). Visualized by SPECT imaging urinary excretion represented the major pathway of elimination for both NP-formulations. In conclusion, this study provides data indicating a positive influence of PEG-derivatization on the biodistribution and pharmacokinetics of Proticles. These results form the basis for further developments as drug delivery and active drug targeting devices.

From nappe stacking to exhumation: Cretaceous tectonics in the Apuseni Mountains (Romania).

New Ar-Ar muscovite and Rb-Sr biotite age data in combination with structural analyses from the Apuseni Mountains provide new constraints on the timing and kinematics of deformation during the Cretaceous. Time-temperature paths from the structurally highest basement nappe of the Apuseni Mountains in combination with sedimentary data indicate exhumation and a position close to the surface after the Late Jurassic emplacement of the South Apuseni Ophiolites. Early Cretaceous Ar-Ar muscovite ages from structurally lower parts in the Biharia Nappe System (Dacia Mega-Unit) show cooling from medium-grade conditions. NE-SW-trending stretching lineation and associated kinematic indicators of this deformation phase (D1) are overprinted by top-NW-directed thrusting during D2. An Albian to Turonian age (110-90 Ma) is proposed for the main deformation (D2) that formed the present-day geometry of the nappe stack and led to a pervasive retrograde greenschist-facies overprint. Thermochronological and structural data from the Bihor Unit (Tisza Mega-Unit) allowed to establish E-directed differential exhumation during Early-Late Cretaceous times (D3.1). Brittle detachment faulting (D3.2) and the deposition of syn-extensional sediments indicate general uplift and partial surface exposure during the Late Cretaceous. Brittle conditions persist during the latest Cretaceous compressional overprint (D4).

Determination of methane emission rates on a biogas plant using data from laser absorption spectrometry.

The aim of the work was to establish a method for emission control of biogas plants especially the observation of fugitive methane emissions. The used method is in a developmental stage but the topic is crucial to environmental and economic issues. A remote sensing measurement method was adopted to determine methane emission rates of a biogas plant in Rhineland-Palatinate, Germany. An inverse dispersion model was used to deduce emission rates. This technique required one concentration measurement with an open path tunable diode laser absorption spectrometer (TDLAS) downwind and upwind the source and basic wind information, like wind speed and direction. Different operating conditions of the biogas plant occurring on the measuring day (December 2013) could be represented roughly in the results. During undisturbed operational modes the methane emission rate averaged 2.8 g/s, which corresponds to 4% of the methane gas production rate of the biogas plant.

A new approach to estimation of methane emission rates from landfills.

Methane emission monitoring has become increasingly essential for diffusive area sources, especially for landfills, which contribute to a significant fraction of the total anthropogenic methane emission globally. Statutorily, methane emission rate from landfills in Germany shall be examined on a semiannual basis; however, an appropriate approach has yet to be developed and adopted for general use. In this study, a new method is proposed based on experimental results, which utilizes a TDLAS (Tunable Diode Laser Absorption Spectroscopy) instrument - GasFinder2.0 system and a dispersion model LASAT (Lagrangian Simulation of Aerosol Transport) as the measurement device and calculation model, respectively. Between April 2010 and December 2011, a research project was conducted at a pilot scale landfill in the south of Germany. Drawing on the extensive research into this pilot project, an effective strategy of measurement setup was determined. Methane concentration was measured with GasFinder2.0 system in the upstream and downstream sections of the project site, while wind and turbulence data were measured simultaneously by an ultrasonic anemometer. The average methane emission rate from the source can be calculated by using the results as input data in the dispersion model. With this method, site-specific measurement approaches can be designed for not only landfills, but also different diffusive area sources with less workload and lower cost compared to conventional FID (Flame Ionization Detector) method.

18F-FDG PET/CT for staging of penile cancer.

UNLABELLED: The value of PET or PET/CT with (18)F-FDG for the staging of penile cancer has yet to be determined. The objective of this study was to investigate the pattern of (18)F-FDG uptake in the primary malignancy and its metastases and to determine the diagnostic value of (18)F-FDG PET/CT in the staging and restaging of penile cancer. METHODS: Thirteen patients (mean +/- SD age, 64 +/- 14.0 y) with suspected penile cancer or suspected recurrent disease were examined with a Gemini PET/CT system (200 MBq of (18)F-FDG). The reference standard was based on histopathologic findings obtained at biopsy or during surgery. RESULTS: Both the primary tumor and regional lymph node metastases exhibited a pattern of (18)F-FDG uptake typical for malignancy. Sensitivity in the detection of primary lesions was 75% (6/8), and specificity was 75% (3/4). On a per-patient basis, sensitivity in the detection of lymph node metastases was 80% (4/5), and specificity was 100% (8/8). On a nodal-group basis, PET/CT showed a sensitivity of 89% (8/9) in the detection of metastases in the superficial inguinal lymph node basins and a sensitivity of 100% (7/7) in the deep inguinal and obturator lymph node basins. The mean +/- SD maximum standardized uptake value for the 8 primary lesions was 5.3 +/- 3.7, and that for the 16 lymph node metastases was 4.6 +/- 2.0. CONCLUSION: According to our results, the main indication for (18)F-FDG PET in the primary staging or follow-up of penile cancer patients may be the prognostically crucial search for lymph node metastases. With the use of a PET/CT unit, the additional information provided by CT may be especially useful for planning surgery. Implementing (18)F-FDG PET and PET/CT in future staging algorithms may lead to a more precise and stage-appropriate therapeutic strategy. Furthermore, invasive procedures with a high morbidity rate, such as general bilateral lymphadenectomy, may be avoided.

Chaotic collisionless evolution in galaxies and charged-particle beams.

Both galaxies and charged particle beams can exhibit collisionless evolution on surprisingly short time scales. This can be attributed to the dynamics of chaotic orbits. The chaos is often triggered by resonance caused by time dependence in the bulk potential, which acts almost identically for attractive gravitational forces and repulsive electrostatic forces. The similarity suggests that many physical processes at work in galaxies, although inaccessible to direct controlled experiments, can be tested indirectly via controlled experiments with charged particle beams, such as those envisioned for the University of Maryland electron ring currently nearing completion.